Exposure to environmental chemicals during critical periods of early development may play an important role in cancer susceptibility later in life. We hypothesize that exposure to estrogenically-active chemicals alone, and in combination, during early critical periods of development will alter predisposition for breast cancer. We propose to investigate the potential of environmental chemicals (for example, TCDD, Bisphenol A, butyl benzyl phthalate and diethylstilbesterol) that are known endocrine disruptors, and one nutritional agent (genistein) that has been demonstrated to protect against breast cancer, when exposure occurs alone and in combination to alter mammary cancer susceptibility. Combinational exposure may result in additive, synergistic or antagonistic results to alter genomic/proteomic expressions that can predispose for breast cancer. The specific aims are: 1: To determine the effects of prenatal and prepubertal exposures to hormonally-active xenobiotics such as TCDD, Bisphenol A, butyl benzyl phthalate, genistein and DES on the proteomic and genomic signatures of rat mammary glands during critical stages of development and differentiation. It is expected that each of these chemicals will alter gland development and differentiation, and modify the genomic and proteomic signatures of the mammary gland. This should provide clues on pathways (functional genomics and proteomics) responsible of modulating the susceptibility and or refractoriness of the mammary tissue to carcinogenesis. These studies will be carried out in mammary glands of control and xenobiotic treated 21, 35, 50 and 100 day old female rats. 2: To determine the effects of prenatal and prepubertal exposures to these hormonally active xenobiotics for predisposition to 7,12-dimethylbenz(a)anthracene induced mammary cancer with the emphasis being timing of exposure to the selected xenobiotics being responsible for altering susceptibility. Changes in susceptibility to mammary cancer will be correlated with gland development and differentiation, and genomic and proteomic signatures. 3: To identify protein biomarkers in the serum of rats taken at different stages of mammary development and following exposure to hormonally-active xenobiotics, and correlate these with serum of human samples collected in Project 2. Serum will be collected from control and xenobiotic-treated animals and analyzed using mass spectrometry to identify protein biomarkers that indicate exposure, developmental stage, and susceptibility for mammary cancer development.